S 18986

DRUG FOCUS: S 18986: A positive allosteric modulator of AMPA-type glutamate receptors pharmacological profile of a novel cognitive enhancer.[Pubmed:21050420]

CNS Neurosci Ther. 2010 Oct;16(5):e193-212.

Alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) type glutamate receptors are critical for synaptic plasticity and induction of long-term potentiation (LTP), considered as one of the synaptic mechanisms underlying learning and memory. Positive allosteric modulators of AMPA receptors could provide a therapeutic approach to the treatment of cognitive disorders resulting from aging and/or neurodegenerative diseases, such as Alzheimer disease (AD). Several AMPA potentiators have been described in the last decade, but for the moment their clinical efficacy has not been demonstrated due to the complexity of the target, AMPA receptors, and the difficulty in studying cognition in animals and humans. A better understanding of the mechanism of action of this type of drug remains an important issue, if knowledge of these compounds is to be increased and if this novel therapeutic approach is to be an interesting research area. Among the AMPA potentiators, S 18986 is emerging as a new selective positive allosteric modulator of AMPA-type glutamate receptors. S 18986, as with other positive AMPA receptor modulators, increased induction and maintenance of LTP in the hippocampus as well as the expression of brain-derived neurotrophic factor (BDNF) both in vitro and in vivo. Its cognitive-enhancing properties have been demonstrated in various behavioral models (procedural, spatial, "episodic," working, and relational/declarative memory) in young-adult and aged rodents. It is interesting to note that memory-enhancing effects appeared more robust in middle-aged animals compared with aged ones and in "episodic" and spatial memory tasks. From these results, S 18986 is expected to treat memory deficits associated with early cerebral aging and neurological diseases in elderly people.

The AMPA modulator S 18986 improves declarative and working memory performances in aged mice.[Pubmed:18469541]

Behav Pharmacol. 2008 May;19(3):235-44.

The aim of this study was to further characterize the memory-enhancing profile of S 18986 a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. S 18986 was studied in two mouse models of age-related memory deficits, using radial maze paradigms involving long-term/declarative memory and short-term/working memory. Aged mice exhibited severe deficits when compared with their younger counterparts in the two behavioural tests. S 18986 at the dose of 0.1 mg/kg selectively improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on short-term retention of successive arm-visits in the short-term/working memory test. This study confirms the memory-enhancing properties of S 18986 and, in line with emerging data on multiple AMPA modulators, highlights the relevance of targeting AMPA receptors in the development of new memory enhancers.

Effects of the AMPA receptor modulator S 18986 on measures of cognition and oxidative stress in aged rats.[Pubmed:18762915]

Psychopharmacology (Berl). 2009 Jan;202(1-3):225-35.

RATIONALE: Development of cognitive-enhancing drugs that delay or halt mild cognitive impairment progression to Alzheimer's disease would be of great benefit. OBJECTIVES: The aim of this study was to examine the ability of (S)-2,3-dihydro-[3,4]-cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S 18986), a positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, to improve behavioral performance and alleviate age-related deficits in oxidative stress status in the prelimbic cortex and hippocampus. MATERIALS AND METHODS: Daily administration of S 18986 (0.1, 0.3, and 1.0 mg/kg) or vehicle was given to separate groups of male rats starting at 12 months of age. Additionally, daily vehicle administration was given to a group of rats starting at 3 months of age. Four months after initiation of drug administration, rats were trained and tested in an operant-delayed alternation task and a reinforcer devaluation task. Upon completion of testing, oxidative stress status was assessed in the prelimbic cortex and hippocampus. RESULTS: S 18986 dose-dependently altered responses in the reinforcer devaluation task such that aged rats came to resemble young rats. There were no age or drug effects in the operant-delayed alternation task. Levels of the lipid peroxidation product 4-hydroxy-nonenal (HNE) were increased, and Cu/Zn-superoxide dismutase (SOD) levels were decreased in prelimbic cortex in aged rats, changes that were reversed by S 18986. Similarly, age-related increases in hippocampal HNE levels were prevented by S 18986. CONCLUSIONS: Positive modulation of AMPA receptor activity may be a therapeutic approach to halt or slow progression of mild cognitive impairment via improvement in oxidative stress status in the hippocampus and prelimbic cortex.

S 18986 reverses spatial working memory impairments in aged mice: comparison with memantine.[Pubmed:21274701]

Psychopharmacology (Berl). 2011 Jun;215(4):709-20.

RATIONALE: Normal or pathological ageing is characterized by working-memory dysfunction paired with a marked reduction in several neurotransmitters activity. The development of therapeutic strategy centered on the glutamatergic system known to bear a critical role in cognitive functions, is therefore of major importance in the treatment of mild forms of AD or age-related memory dysfunctions. OBJECTIVES: In Experiment 1, we investigated the effects of ageing on spatial working memory measured by sequential alternation (SA). Thus, the decay of alternation rates over a series of trials separated by varying intertrial temporal intervals (ITI, from 5 sec to 180 sec) was studied in mice of different age groups. In Experiment 2, we investigated the memory-enhancing potential of S 18986--a modulator of AMPA receptors--on age-related SA impairments, in comparison with memantine--an antagonist of NMDA receptors--. RESULTS: In Experiment 1, aged mice responded at chance with shorter ITI's and exhibited greater levels of interference in the SA task as compared to young adult mice. In Experiment 2, (1) S 18986 at 0.03 and 0.1 mg/kg reversed the memory deficit in aged mice but did not modify performance in young adult mice; (2) memantine at 10 mg/kg also increased SA rates in aged mice but did not improve performance in young adult mice. CONCLUSION: The SA task is a useful tool to reveal age-induced time-dependent working memory impairments. As compared to memantine, S 18986--a compound targeting AMPA receptors--contributes a valuable therapy in the treatment of age-related cognitive dysfunctions or mild forms of AD.

Neuropharmacokinetics of a new alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) modulator, S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], in the rat.[Pubmed:15860654]

Drug Metab Dispos. 2005 Aug;33(8):1137-43.

The aim of our study was to determine the neuropharmacokinetics of S18986 [(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide], a new positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type receptors, in the rat. We focused on its blood-brain barrier (BBB) uptake and on its brain intra- and extracellular fluid (bICF-bECF) partitioning. BBB transport of S18986 was measured using the in situ brain perfusion technique. bECF concentrations were determined by microdialysis in the two effector areas, i.e., frontal cortex (FC) and dorsal hippocampus (DH), and blood samples were collected simultaneously through a femoral catheter. Cerebrospinal fluid and brain tissue concentrations were determined using a conventional pharmacokinetic approach. Using all the experimental data, pharmacokinetic modeling was applied to describe the S18986 blood-brain disposition. The brain uptake clearance of S18986 was found to be high, about 20 mul s(-1) g(-1). Terminal half-lives were similar in plasma and brain, at around 1 h. Experimental and predicted blood and brain concentrations were a good fit with the pharmacokinetic model, which assumed first-order rate constants at each interface. Ratios of bECF to the unbound plasma area under the curve (AUC) were 0.24 in FC and 0.25 in DH, whereas ratios of bICF/plasma AUC were 1 in FC and 1.5 in DH. We conclude that despite the ratio of bECF/plasma AUC below 1, there is nevertheless an elevated BBB uptake of S18986. This can be explained by the S18986 nonhomogenous bECF/bICF partitioning, since S18986 mainly distributes into hippocampal bICF. This illustrates the importance of taking bECF/bICF partitioning into account when interpreting the neuropharmacokinetics of a drug.

(S)-2,3-dihydro-[3,4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide: (S18986-1) a positive modulator of AMPA receptors enhances (S)-AMPA-mediated [3H]noradrenaline release from rat hippocampal and frontal cortex slices.[Pubmed:10924919]

Eur J Pharmacol. 2000 Aug 4;401(2):145-53.

The present study describes the effect of (S)-2,3-dihydro-[3, 4]cyclopentano-1,2,4-benzothiadiazine-1,1-dioxide (S18986-1), a positive allosteric modulator of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors with cognitive-enhancing effects, on (S)-AMPA-induced [3H]noradrenaline release in rat hippocampal and frontal cortex slices. (S)-AMPA significantly increased [3H]noradrenaline release in rat hippocampus and frontal cortex slices, whereas S18986-1 (3-1000 microM) alone, was inactive. However, S18986-1 between 30 and 1000 microM potently enhanced (+200%) (S)-AMPA-mediated [3H]noradrenaline release in both hippocampal and frontal cortex slices. The capacity of S18986-1 to potentiate [3H]noradrenaline release was specific for AMPA receptors as S18986-1 failed to potentiate either kainate and N-methyl-D-aspartate (NMDA)-mediated release of [3H]noradrenaline in rat hippocampal slices. Moreover, 1, 2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX) and 1-(4-aminophenyl)-3-methylcarbamoyl-4-methyl-3, 4-dihydro-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI-53655) but not (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine ((+)-MK-801), inhibited (S)-AMPA and S18986-induced stimulation of (S)-AMPA-mediated [3H]noradrenaline release. In addition, S18986-1-induced stimulation of (S)-AMPA-evoked [3H]noradrenaline release was markedly attenuated in the presence of tetrodotoxin (1 microM) and in Ca(2+)-free buffer. S18986-1 enhanced (S)-AMPA-mediated [3H]noradrenaline release to a greater extent than its corresponding (R)-enantiomer S19024-1 and racemic mixture S17951-1. However, positive allosteric modulators of AMPA receptors such as aniracetam failed to potentiate AMPA-mediated noradrenaline release in hippocampal slices, whereas cyclothiazide potently enhanced (S)-AMPA-mediated [3H]noradrenaline release. These results suggest that the capacity of S18986-1 to enhance AMPA receptor-mediated release of noradrenaline in rat hippocampus and frontal cortex, could contribute to the cognition enhancing mechanisms of S18986-1.

S 18986 is a selective, orally active, brain penetrant positive allosteric modulator of AMPA-type receptors. S 18986 shows cognitive enhancing properties in rodents. S 18986 activates the release of noradrenaline and acetylcholine in rat hippocampus and enhances rat memory in object-recognition tests.

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